Bone morphogenetic protein signaling is required for RAD51-mediated maintenance of genome integrity in vascular endothelial cells

Abstract

The integrity of blood vessels is fundamental to vascular homeostasis. Inactivating mutations in the bone morphogenetic protein (BMP) receptor type II (BMPR2) gene cause hereditary vascular disorders, including pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia, suggesting that BMPR2 and its downstream signaling pathway are pivotal to the maintenance of vascular integrity through an unknown molecular mechanism. Here we report that inactivation of BMPR2 in pulmonary vascular endothelial cells results in a deficit of RAD51, an enzyme essential for DNA repair and replication. Loss of RAD51, which causes DNA damage and cell death, is also detected in animal models and human patients with pulmonary arterial hypertension. Restoration of BMPR2 or activation of the BMP signaling pathway rescues RAD51 and prevents DNA damage. This is an unexpected role of BMP signaling in preventing the accumulation of DNA damage and the concomitant loss of endothelial integrity and vascular remodeling associated with vascular disorders.

DNA Damage and Repair in Pulmonary Arterial Hypertension

“…The results also validated with small interfering RNA (siRNA) revealed enhanced expression of CHK-1 upregulates RAD-51 [ 73 ]. This contrasts with the findings in PAECs in a separate study, where BMPR2-deficient PAECs showed a reduced level of RAD51 and lung tissue from IPAH patients had attenuated RAD51 levels [ 77 ]. In vivo studies supported the therapeutic potential of the CHK-1 inhibitor by reducing the hemodynamic parameters associated with increased DNA damage in fawn-hooded rats with already developed PAH; however, no reduction in RV hypertrophy was observed [ 73 ].…”

“…Consistent with the downregulation of BMPR2 under a DNA-damaging environment, Vattulainen-Collanus and colleagues uncovered a previously unknown role of BMP signaling in the protection of cells from genomic insult [ 77 ]. They showed that MMC treatment reduced the expression of BMPR2, BRCA1, and RAD51.…”

“…Importantly, however, the types of DNA damage most prevalent in PAH and their cause(s) remain to be fully determined. Some studies suggest that the downregulation of BMPR2 may play a pivotal role in DNA damage [ 77 , 89 ], yet the incidence of DNA damage measured by micronucleus assay and γH2AX staining trended lower in HPAH cells compared with APAH-CHD [ 46 ], emphasizing that gaps in knowledge remain.…”

“…DDR inhibitors have shown some success, but the additional damage and associated detrimental effects on health across different vascular compartments cannot be ignored [ 49 , 67 , 70 , 73 ]. It is important to note that, by necessity, the majority of these studies are performed on PAH-vascular cells, PAECs and PASMCs, derived from end-stage tissues, since such cells cannot be obtained at earlier stages of the disease [ 39 , 40 , 42 , 44 , 45 , 46 , 47 , 48 , 49 , 61 , 66 , 67 , 70 , 73 , 77 , 78 , 88 , 89 ]. The dysfunctional DDR or augmented DNA damage could be the result of surrounding variables like inflammation, hypoxia etc.…”

“…To validate the in vitro results, the role of RAD-51 was studied in BMPR2 R899X/+ mice, which develop mild PH beyond 6 months [ 91 ]. It was observed that RAD51 expression was repressed in PMVECs and PASMCs extracted from BMPR2 R899X/+ mice as compared to control mice, suggesting a regulatory link between BMPR2 and RAD51 [ 77 ]. Similarly, lung sections from IPAH patients had a significant reduction of RAD51 in the endothelium of pulmonary arteries compared to control samples.…”